Tag: Medication

Research headed by a team at Stanford Medicine has identified two proteins with opposing functions that are involved in orchestrating the development and maintenance of healthy skin.

The proteins, NEDD8 and SUMO2, are part of a family called ubiquitin-like proteins (UBLs), and the researchers believe that modulating their activity with topical drugs could reduce inflammation, aid wound healing, and slow or halt the growth of skin cancer.

“These two ubiquitin-like protein systems are remarkably dedicated and opposite in their functions,” said Paul Khavari, MD, PhD, chair of dermatology at the Stanford School of Medicine and senior author of the study. “One promotes the stem-cell state while the other drives differentiation. It’s like having two opposing forces that determine a cell’s fate.”

Added clinical instructor of dermatology Mårten Winge, MD, PhD, “What’s really exciting is how specific these effects are. When we manipulate one system or the other, we see very clear and opposite outcomes. This specificity is unusual for ubiquitin-like pathways and makes these systems particularly attractive for therapeutic targeting.”

Khavari, who is the Carl J. Herzog Professor in Dermatology in the School of Medicine, chief of dermatology at Veterans Affairs Palo Alto, and a member of the Stanford Cancer Institute, is senior author, and Winge is co-lead author of the researchers’ published paper in Science, titled “Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation.” The work was carried out in collaboration with researchers at Icahn School of Medicine at Mount Sinai.

Stratified epithelial tissues, such as the skin’s epidermis, differentiate to form protective barriers against environmental attacks, the authors wrote. “This process involves coordinated modulation of thousands of genes and is disrupted in many inflammatory or neoplastic diseases.

Ubiquitination controls the targeted destruction and disposal of unneeded proteins in a cell. “Ubiquitin and related ubiquitin-like proteins (UBLs) comprise a major layer of protein regulation,” the team continued. The study by Khavari and colleagues has now found that in the skin, certain ubiquitin-like proteins switch on or off wide swaths of genes involved in cellular growth and development. In particular, they trigger progenitor, or stem, cells in the lower layer of the skin to either mature and migrate to the skin surface or to self-renew.

The outer layer of your skin can be considered as two distinct compartments. On the lower level, progenitor cells or skin-specific stem cells wait to transform into keratinocytes, a more specialized cell type forming the critical skin barrier that keeps moisture in (and out),  excludes infection-causing pathogens, repels DNA-damaging ultraviolet rays, and harbors the nerve endings that allow us to sense our surroundings.

These progenitor cells divide just enough to keep their numbers robust. But when needed—after injury or infection or when skin cells naturally slough off—a subset of progenitor cells differentiate and migrate to the skin’s surface. Disruptions in this delicate balance between stem cell maintenance and their maturation into adult keratinocytes can lead to psoriasis, poor wound healing, and skin cancer.

The researchers were interested in understanding how the differentiation switch is flipped. “We hypothesized that differentiation-dependent proteomic remodeling diverges from RNA-level effects due to posttranslational protein modifications,” they noted. They used a wide swath of experimental approaches to assess dynamic changes in the expression of thousands of genes and proteins at various stages of keratinocyte differentiation. The results found that the maturing cells expressed increasing levels of genes and proteins involved in skin formation and decreasing levels of others associated with stem cell maintenance. Many of the proteins that decreased during differentiation bore small molecular tags that identify locations recognized by other proteins in the ubiquitin pathways—giving a hint that ubiquitination may be involved in the differentiation switch the researchers were seeking.

Disrupting the expression of more than 200 genes in the ubiquitin pathway during keratinocyte maturation highlighted two subpathways essential for proper differentiation: NEDDylation and SUMOylation. Hobbling the NEDDylation pathway supercharged differentiation, while blocking SUMOylation prevented differentiation. Similar results were obtained when the pathways were blocked pharmacologically with existing drugs in both human keratinocytes grown in the laboratory and in human skin organoids—three-dimensional sheets of tissue about the size of a quarter that mimic the multicellular structure of human skin.

Next, the researchers genetically engineered laboratory mice such that the expression of either Nedd8 or Sumo2—two key proteins in the NEDDylation and SUMOylation pathways—could be blocked when a triggering molecule is applied to the animals’ skin. They found that the skin of the mice developed abnormally when either Nedd8 or Sumo2 expression was halted, showing that both proteins are necessary for proper skin development.

“Generation of conditional knockout mice established essential roles for NEDD8 in progenitor maintenance, skin regeneration, and inflammation, whereas SUMO2 was required for differentiation,” they commented. Mice unable to make Nedd8 had an overgrowth of keratinocytes on their skin’s surface (similar to psoriasis), and animals lacking Sumo2 showed impaired differentiation and a loss of the distinct layers that make up healthy skin.

In addition to changes in the skin cells, the loss of Nedd8 and Sumo2 led to striking changes in the amounts and kinds of immune cells populating the skin. Nedd8 loss resulted in an increase in the numbers of immune cells called neutrophils in the skin and caused inflammation, while Sumo2 loss caused an increase in the numbers of another immune cell called a T cell. “In skin, NEDD8 maintained the undifferentiated epidermal state, enabled wound healing, and restrained neutrophilic inflammation,” they said. “SUMO2 promoted proper epidermal differentiation and suppressed T lymphocyte infiltration.”

Khavari commented: “We’re not just changing individual cells—we’re changing the whole tissue microenvironment. Manipulating these pathways could have therapeutic applications for wounds, inflammation, skin aging, and even cancer.”

Further experiments showed that the effect of Nedd8 on cell differentiation is due to its association with an RNA-binding protein called HNRNPU. “NEDD8 loss modulated the RNA binding and stabilizing functions of HNRNPU,” the team explained. In the absence of Nedd8, HNRNPU latches onto and stabilizes sets of RNA messages encoding genes for proteins essential for the differentiation of progenitor cells into keratinocytes, but when Nedd8 attaches to HNRNPU, the protein instead binds to and stabilizes RNA messages encoding proteins necessary for progenitor cell maintenance.

“Thus, NEDD8 and SUMO2 play opposite roles in epithelial homeostasis, regeneration, and inflammation, demonstrating multiple ways ubiquitin-like networks govern tissue homeostasis,” the team reported in their paper. “The researchers are now exploring whether topical drug treatments targeting the NEDDylation or SUMOylation pathways could tilt the balance of keratinocyte differentiation to progenitor cell maintenance and to treat a variety of skin diseases and disorders.

“The beauty of understanding these fundamental switches is that we can apply them to multiple disease states,” said co-lead author Leandra Jackrazi, an MD/PhD student. “Whether it’s promoting wound healing, reducing inflammation, or controlling cancer growth, having the ability to toggle between stemlike and differentiated states opens many doors.”

The post Two Proteins with Opposing Functions Found to Support Healthy Skin Maintenance appeared first on GEN – Genetic Engineering and Biotechnology News.

A protein best known for helping neurons communicate may also help Alzheimer’s disease pathology move through the brain, according to new research from University of Utah Health.

The study, published in Cell, identifies the neuronal protein Arc as a key factor that helps toxic tau move from diseased neurons into neighboring healthy cells. In mouse models, removing Arc sharply reduced the transfer of tau between brain cells, pointing to a potential new strategy for slowing disease progression rather than reversing damage that has already occurred.

“I’m excited by the fact that we’ve identified a new way of potentially stopping the progression of Alzheimer’s disease,” said Jason Shepherd, PhD, professor of neurobiology at University of Utah Health and senior author of the study.

A new route for tau spread

Alzheimer’s disease is marked by the accumulation of abnormal protein deposits, including amyloid plaques and tau tangles. While amyloid has historically dominated drug development, tau pathology is closely linked to neurodegeneration and cognitive decline. As tau spreads across connected brain regions, symptoms worsen, making the mechanisms of tau transmission a major focus for therapeutic research.

The new study centers on Arc, a protein involved in synaptic plasticity, memory formation, and communication between neurons. Arc can package itself into extracellular vesicles, small membrane-bound particles that move between cells and carry biological cargo.

The researchers found that tau can use this system to its advantage. In Alzheimer’s mouse models, Arc helped package tau into extracellular vesicles, allowing tau to move from one neuron to another. Once taken up by recipient neurons, tau seeds can corrupt normal tau and trigger new aggregation.

By comparing Alzheimer’s model mice with and without Arc, the team showed that Arc was required for efficient tau release in neuronal extracellular vesicles and for tau transmission between cells.

The ‘glue monster’ problem

Tau is normally present in neurons and helps support microtubules, structures that act like internal transport tracks. In Alzheimer’s disease and related tauopathies, tau becomes abnormally modified, misfolds, and forms aggregates that interfere with neuronal function.

Mitali Tyagi, PhD, first author of the study and now a postdoctoral research associate at Washington University in St. Louis, compared tau tangles to “glue monsters.”

“They glue together and block transportation within the neuron,” Tyagi said. “But they can break down into smaller glue monsters, called tau seeds, which can then get transferred to a new neuron. And once this tau seed comes into contact with healthy tau, it is able to corrupt it. So, the pathology starts all over again in a healthy neuron.”

The researchers found extracellular vesicles containing both Arc and tau in the brains of Alzheimer’s model mice. These vesicles could seed tau aggregation in cell-based assays. But when Arc was absent, the vesicles contained far less tau and had greatly reduced seeding activity.

“When we removed Arc, we saw that the transfer of tau was severely, severely reduced,” Tyagi said. “It was almost gone.”

A double role for Arc

The findings are not as simple as suggesting Arc should be eliminated entirely. Arc appears to play a double-edged role in Alzheimer’s biology.

On one hand, Arc helps neurons export tau, which may reduce toxic buildup inside the original diseased cell. On the other hand, that same export process allows tau to reach and damage neighboring neurons.

“When Arc is absent, tau becomes trapped inside neurons and accumulates to toxic levels. When Arc is present, tau can be released in extracellular vesicles. While this helps reduce tau buildup within the original neuron, the released tau can be taken up by neighboring healthy neurons, promoting the spread of pathology,” Tyagi said.

In mice lacking Arc, tau accumulated inside neurons and was associated with early signs of cell toxicity. Yet tau transfer between cells was markedly reduced. This suggests that simply blocking tau release may not be the best therapeutic approach, because it could worsen toxicity in neurons already burdened by tau.

Instead, the researchers suggest that a more precise strategy may be to intercept tau-containing vesicles after they leave sick neurons but before they enter healthy ones.

Human brain data support the mechanism

Although much of the work was done in mice and cell models, the team also examined human postmortem brain tissue. They found that human brain-derived extracellular vesicles contained both Arc and phosphorylated tau, a disease-associated form of the protein.

The study also reported a positive correlation between Arc levels and phosphorylated tau levels in extracellular vesicles isolated from human brain tissue, supporting the idea that Arc-mediated vesicle biology may be relevant to human disease.

However, the authors caution that the work is still early. The strongest causal evidence comes from mouse models, and more research is needed to determine whether the same mechanism drives tau spread in people with Alzheimer’s disease.

“Most of the work we’ve been doing is in mice, not in humans,” Shepherd said. “We have some clues that whatever is happening in these mice could also be happening in humans, but we don’t know that yet. And we’re far away from saying that we’re developing a treatment for anything. But it could open new avenues to get to that point.”

Toward therapies that slow progression

The findings arrive as Alzheimer’s treatment is beginning to shift from symptom management toward disease modification. Anti-amyloid therapies have shown that changing disease biology is possible, but there remains a major need for treatments that slow tau-driven neurodegeneration and preserve cognition for longer.

Targeting tau spread could be one way to do that. A therapy aimed at tau-containing extracellular vesicles would not be expected to restore neurons already lost to disease. But it could potentially slow the movement of pathology through the brain, especially in early disease stages.

“If we could target these particular EVs, that would be a really useful therapy strategy,” Shepherd said. “For someone with early-onset Alzheimer’s or dementia, if we could stop the spread, then we could prevent further damage and cognitive decline.”

The study positions Arc not only as a messenger of normal brain communication, but also as a possible vehicle for pathological tau spread. The next challenge will be determining whether that vehicle can be safely intercepted without disrupting Arc’s essential roles in memory and synaptic function.

The post Brain Messenger Protein May Help Tau Spread in Alzheimer’s Disease appeared first on Inside Precision Medicine.

Cardiovascular disease is often managed through broad clinical categories: heart failure, cardiomyopathy, ischemic injury, arrhythmia risk. These categories are essential for diagnosis and treatment, but they do not fully explain why patients with similar clinical presentations can progress differently or respond unevenly to therapy.

A new single-nucleus atlas of the adult human heart aims to bring that biology into sharper focus. In a study published in Nature Cardiovascular Research, researchers from the Broad Institute of MIT and Harvard and Mass General Brigham developed HeartMap, an integrated atlas spanning more than 2.4 million cardiac nuclei from 209 individuals.

The resource brings together data from nine studies and includes eight anatomical regions and seven healthy or disease states. Its value lies not only in scale, but in its attempt to make cardiac single-cell data more comparable across studies.

Why cardiology needs cellular resolution

Precision medicine depends on identifying the biological mechanisms that matter for a specific patient or disease subtype. In oncology, this has increasingly meant matching molecular alterations to targeted therapies. Cardiology has made important progress with genetics, imaging, biomarkers, and risk stratification, but many therapeutic decisions still operate at a relatively high level of disease classification.

Heart disease is not driven by cardiomyocytes alone. Fibroblasts, endothelial cells, immune cells, vascular smooth muscle cells, pericytes, and other populations all contribute to remodeling, inflammation, fibrosis, and tissue dysfunction. A patient’s clinical phenotype may therefore reflect different combinations of cellular programs.

HeartMap was designed to help researchers interrogate those programs. The authors write that differentiating transcriptional signatures between cardiovascular disease groups using HeartMap “may aid in precision medicine approaches” by informing biomarker and therapeutic target discovery.

Separating robust disease signals from dataset noise

Single-cell and single-nucleus sequencing have already revealed important differences between healthy and diseased cardiac tissue. However, individual studies vary in how samples are collected, processed, sequenced, and analyzed. Those differences can obscure whether a signal is truly disease-related or specific to a cohort or protocol.

To address this, the HeartMap team reprocessed and harmonized published datasets, using computational integration to reduce technical variation while preserving biological signal. The final atlas resolved 14 broad cardiac cell types and 52 clusters.

Across the atlas, diseased and non-failing hearts separated by gene expression patterns. Disease-versus-control comparisons produced more differentially expressed genes than comparisons between disease states, suggesting that different cardiovascular conditions share broad remodeling programs while retaining more specific molecular features.

That distinction is important for translation. Shared injury programs may help explain common features of heart failure progression, while disease-specific or cell-state-specific programs may point to more selective therapeutic opportunities.

Fibroblasts show why cell state matters

One of the most clinically relevant findings involves fibroblasts. These cells are central to fibrosis and cardiac remodeling, but they are not a single uniform target. Some fibroblast activity may be part of necessary repair, while other states may contribute to scar formation, tissue stiffening, inflammation, and progressive dysfunction.

HeartMap identified 29 fibroblast subclusters, including activated fibroblast populations that differed across cardiomyopathies. Two activated populations, enriched for COL22A1 or TNC, were validated in human heart tissue using RNAscope.

This matters because anti-fibrotic drug development has long faced a precision problem: suppressing fibrosis broadly may not be the same as targeting the cell states that drive pathological remodeling. The authors note that identifying these activated fibroblast populations brings the field closer to understanding which subpopulations are “ideal candidates for therapeutic intervention.”

A research reference, not a clinical test

HeartMap is not a diagnostic assay and is not ready to guide care for individual patients. The atlas is built from previously generated datasets, so the researchers could not fully control sample collection, nuclei isolation, sequencing methods, or clinical metadata. The study also notes limited ancestral diversity, with samples largely from White or unclassified ethnic backgrounds. Most disease samples represented chronic or end-stage disease, limiting insight into early disease initiation.

Even so, the atlas points to an important direction for precision cardiology. Future patient datasets could be compared against resources such as HeartMap to determine which cellular programs are active in a given disease context. Over time, that could help connect clinical phenotypes with cell-specific biomarkers, drug targets, and mechanisms of progression.

Rather than treating the diseased heart as a single failing organ, HeartMap frames it as a dynamic cellular system. That shift may be essential if cardiovascular medicine is to move beyond broad disease labels toward therapies guided by the cells and pathways driving disease in individual patients.

The post HeartMap Atlas Offers New Single-Cell View of Human Heart Disease appeared first on Inside Precision Medicine.